Akt kinase C-terminal modifications control activation loop dephosphorylation and enhance insulin response.
Publication/Presentation Date
10-1-2015
Abstract
The Akt protein kinase, also known as protein kinase B, plays key roles in insulin receptor signalling and regulates cell growth, survival and metabolism. Recently, we described a mechanism to enhance Akt phosphorylation that restricts access of cellular phosphatases to the Akt activation loop (Thr(308) in Akt1 or protein kinase B isoform alpha) in an ATP-dependent manner. In the present paper, we describe a distinct mechanism to control Thr(308) dephosphorylation and thus Akt deactivation that depends on intramolecular interactions of Akt C-terminal sequences with its kinase domain. Modifications of amino acids surrounding the Akt1 C-terminal mTORC2 (mammalian target of rapamycin complex 2) phosphorylation site (Ser(473)) increased phosphatase resistance of the phosphorylated activation loop (pThr(308)) and amplified Akt phosphorylation. Furthermore, the phosphatase-resistant Akt was refractory to ceramide-dependent dephosphorylation and amplified insulin-dependent Thr(308) phosphorylation in a regulated fashion. Collectively, these results suggest that the Akt C-terminal hydrophobic groove is a target for the development of agents that enhance Akt phosphorylation by insulin.
Volume
471
Issue
1
First Page
37
Last Page
51
ISSN
1470-8728
Published In/Presented At
Chan, T. O., Zhang, J., Tiegs, B. C., Blumhof, B., Yan, L., Keny, N., Penny, M., Li, X., Pascal, J. M., Armen, R. S., Rodeck, U., & Penn, R. B. (2015). Akt kinase C-terminal modifications control activation loop dephosphorylation and enhance insulin response. The Biochemical journal, 471(1), 37–51. https://doi.org/10.1042/BJ20150325
Disciplines
Medicine and Health Sciences
PubMedID
26201515
Department(s)
Department of Medicine
Document Type
Article